Therapy for the treatment of disease

ABSTRACT

Disclosed herein are pharmaceutical compositions comprising oxybutynin, or a free base thereof or a pharmaceutically acceptable salt thereof, and pilocarpine, or a free base thereof or a pharmaceutically acceptable salt thereof. Also disclosed are methods of treating a patient suffering from overactive bladder comprising administering to the patient the above pharmaceutical composition.

RELATED APPLICATION

This application is a continuation of U.S. application Ser. No.11/467,760, filed, Aug. 28, 2006, by Mehdi Paborji, and entitled“THERAPY FOR THE TREATMENT OF DISEASE,” which in turn claims priority toU.S. Provisional Application No. 60/714,150, filed Sep. 2, 2005, byMehdi Paborji, and entitled “THERAPY FOR THE TREATMENT OF DISEASE,” bothof which are incorporated herein by reference in their entirety.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention is in the field of pharmaceutical compositions andmethods of using the same for the treatment of overactive bladder andreduction of various side effects thereof.

2. Description of the Related Art

Overactive bladder (OAB) is characterized by involuntary contractions ofthe detrusor muscle during bladder filling. These contractions may beasymptomatic or may cause the three common symptoms that clinicallydefine OAB: frequency of urination; urgency; and urge, or reflex,incontinence. Frequency is an increase in the number of micturitions, toas many as eight or more a day. Urgency is the strong and sudden desireto urinate. Urge incontinence, or reflex incontinence, is the situationwhere the urge to urinate cannot be controlled. Nocturia, or nighttimeurinary frequency that disturbs sleep (more than twice a night), isoften included as a fourth symptom. The symptoms of OAB may appearindividually or together, and it is not known whether they have apathologic or neurogenic cause.

Incontinence is present in over half of female patients with OAB. Thiscondition affects more than 33 million Americans and imposesconsiderable economic, social, and psychological burdens. Althoughcontinued research in the pharmacologic management of lower urinarytract disorders have led to alternative treatment options, the symptomsof OAB are generally underreported by patients and under-treated byhealthcare professionals.

Several classes of medications have been used to treat and manage OAB,including calcium channel blockers, tricyclic antidepressants,alpha-adrenergic antagonists, estrogen, and anticholinergic agents.Anticholinergic agents, which exert their effects at muscarinicreceptors and suppress or diminish the intensity of involuntary detrusormuscle contractions, are the first-choice pharmacotherapy for OAB, andmay be the only therapy available whose efficacy is not in question.Oxybutynin chloride and tolterodine tartrate are the most extensivelystudied of the anticholinergic agents, and the most widely used. Arecent evidence-based systematic review of controlled clinical trials ofseveral agents concluded that anticholinergic therapies significantlyimproved several indices of lower urinary tract function, includingfrequency of micturition and number of incontinence episodes. A majorlimitation of these agents is that they lack specificity for bladdertissue, with resultant bothersome side effects such as dry mouth andconstipation.

Tolterodine has generally been associated with less dry mouth thanoxybutynin. This property is thought to be due to the decreasedselectivity of tolterodine for any one of the 5 muscarinic receptorsubtypes (M1-M5), such as the M3 receptor that predominates in parotidtissue. Oxybutynin, more than tolterodine, has a high affinity for thisreceptor, which also mediates bladder contraction. It has been argued onthe basis of animal data that tolterodine has a greater selectivity thanoxybutynin for bladder than for parotid muscarinic receptors, but such amechanism remains to be elucidated. Effects on M2 receptors, whichpopulate bladder smooth muscle though not glandular tissue, and forwhich tolterodine shows a greater affinity than oxybutynin, have alsobeen invoked to explain the relatively slightly lower degree of drymouth that is associated with the therapeutic effect of tolterodine.

Additional reports that the higher extent of dry mouth with oxybutyninis attributed to formation of the major metabolite, desethyloxybutynin,which appears to have a greater affinity for the M3 subtype receptorsalso expressed in the salivary glands. However, the newerextended-release formulations of oxybutynin and tolterodine providecomparable or perhaps slightly better efficacy and enhanced tolerabilitycompared with immediate-release formulations. More recently approvedagents including trospium chloride, solifenacin succinate (Vesicare) anddarifenacin (Enablex) appear to have a better side effect profile, i.e.,slightly less dry mouth. Nonetheless, the dry mouth and constipationcontinue to be problematic and patients stop taking the medication aftershort period of therapy.

Thus, there exists a need in the art for a medication that providessufficient efficacy for the treatment of OAB, with much reduced level ofside effects in order to increase patient compliance, comfort, andefficacy.

SUMMARY OF THE INVENTION

Disclosed herein are pharmaceutical compositions comprising atherapeutically effective amount of a first compound and atherapeutically effective amount of a second compound, wherein the firstcompound is an antimuscarinic or an anticholinergic agent and the secondcompound causes stimulation of salivary glands. Also, disclosed hereinare pharmaceutical compositions comprising a therapeutically effectiveamount of a first compound and a therapeutically effective amount of asecond compound, wherein the first compound is an antimuscarinic or ananticholinergic agent and the second compound relieves constipation.Further, disclosed herein are pharmaceutical compositions comprising atherapeutically effective amount of a first compound, a therapeuticallyeffective amount of a second compound, and a therapeutically effectiveamount of a third compound, wherein the first compound is anantimuscarinic or an anticholinergic agent, the second compound causesstimulation of salivary glands, and the third compound relievesconstipation.

Disclosed herein are methods of treating a patient comprisingadministering to a patient in need thereof a therapeutically effectiveamount of a first compound and a therapeutically effective amount of asecond compound, wherein the first compound is an antimuscarinic or ananticholinergic agent and the second compound causes stimulation ofsalivary glands. Also disclosed herein are methods of treating a patientcomprising administering to a patient in need thereof a therapeuticallyeffective amount of a first compound and a therapeutically effectiveamount of a second compound, wherein the first compound is anantimuscarinic or an anticholinergic agent and the second compoundcauses stimulation of salivary glands. Further, disclosed herein aremethods of treating a patient comprising administering to a patient inneed thereof a therapeutically effective amount of a first compound, atherapeutically effective amount of a second compound, and atherapeutically effective amount of a third compound, wherein the firstcompound is an antimuscarinic or an anticholinergic agent, the secondcompound causes stimulation of salivary glands, and the third compoundrelieves constipation.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph showing the amount of saliva flow collected in a humansubject subsequent to the administration of oxybutynin (♦, diamond),pilocarpine (▪, square), both (, circle), and neither (▴, triangle).

FIG. 2 is a graph showing the percentage of saliva flow with referenceto time zero.

FIG. 3 is a graph showing the effect of time delay for theadministration of pilocarpine, with oxybutynin being administered at t=0for all experiments, except for placebo (▴, triangle) where there was nooxybutyin, and pilocarpine being administered at t=0 (▪, square), t=30min (, circle), and t=60 min (♦, diamond).

FIG. 4 is a graph showing the effect of different dose ratios betweenoxybutynin and pilocarpine on saliva flow.

FIG. 5 is a graph showing the comparison of stimulated salivary outputfollowing oral administration of 5 mg oxybutynin (, circle), 30 mgcevimeline (♦, diamond), placebo (♦, triangle), and a combination ofoxybutynin and cevimeline (THVD-102) (▪, square).

FIG. 6 is a graph showing the comparison of stimulated salivary outputfollowing oral administration of 2 mg tolterodine tartrate, with variouscombinations (2 mg tolterodine/5 mg pilocarpine and 2 mg tolterodine/10mg pilocarpine with pilocarpine administered at different times), andplacebo.

FIG. 7 is a graph showing the relationship of time of administration of10 mg of pilocarpine on stimulated salivary output after oraladministration of 2 mg tolterodine tartrate.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The major limitations of treatment of overactive bladder (OAB) are thedry mouth and constipation side effects. The current approach to addressthe dry mouth is development of sustained release of the active moiety,such as oxybutynin or tolterodine. Patients taking OAB medications stillsuffer from these side effects and thus their quality of life ishampered significantly to the extend that majority of patientsdiscontinue the mediations after about 4-6 months.

Thus, in the first aspect, the present invention relates to apharmaceutical composition comprising a therapeutically effective amountof a first compound and a therapeutically effective amount of a secondcompound, wherein the first compound is an antimuscarinic or ananticholinergic agent and the second compound causes stimulation ofsalivary glands.

The first compound of the pharmaceutical compositions described hereinis a compound useful in the treatment of overactive bladder. In someembodiments, the first compound is an agonist of M2 or M3 muscarinicreceptors. In further embodiments, the first compound may be selectedfrom the group consisting of oxybutynin, tolterodine, solifenacin,darifenacin, trospium, fesoterodine, or a pharmaceutically acceptablesalt or prodrug thereof. Other compounds known now or later developedfor the treatment of OAB are within the scope of the present disclosure.

In some embodiments, the first compound is a compound of Formula I

or a pharmaceutically acceptable salt or prodrug thereof, wherein:

R₁-R₉ are each independently selected from the group consisting ofhydrogen, alkyl, nitro, amino, cyano, hydroxy, alkoxy, carboxylate, andamide; and

m and n are each independently selected from 1, 2, 3, 4, and 5.

In some embodiments, each R₁ and R₂ is independently selected from thegroup consisting of hydrogen, alkyl, hydroxy, and alkoxy. In certainembodiments, each R₁ and R₂ is hydrogen.

In some embodiments, R₃ is selected from the group consisting ofhydrogen, alkyl, hydroxy, and alkoxy. In certain embodiments, R₃ ishydroxy.

In some embodiments, R₄ and R₅ are each independently selected from thegroup consisting of hydrogen, alkyl, hydroxy, and alkoxy. In certainembodiments, R₄ and R₅ are each independently an alkyl. In furtherembodiments, R₄ and R₅ are each independently selected from the groupconsisting of methyl, ethyl, propyl, n-butyl, isobutyl, and tert-butyl.In other embodiments, R₄ and R₅ are each independently ethyl.

In some embodiments, R₆-R₉ are each independently selected from thegroup consisting of hydrogen, alkyl, hydroxy, and alkoxy. In certainembodiments, R₆-R₉ are each independently a hydrogen.

In some embodiments, the first compound is oxybutynin, or apharmaceutically acceptable salt or prodrug thereof. Oxybutynin is theactive ingredient found in drugs such as Ditropan®; Ditropan XL®; andOxytrol®. Oxybutynin is an anticholinergic drug, thereby suppressinginvoluntary contractions of the bladder's smooth muscle. Oxybutynin isalso believed to have muscarinic receptor activity, which furtherenhances its OAB efficacy, but also may be the reason behind its mostprevalent side effect, dry mouth.

In some embodiments, the first compound is tolterodine, or apharmaceutically acceptable salt or prodrug thereof. Tolterodine, whichhas the chemical name(R)-2-[3-[bis(1-methylethyl-amino]-1-phenylpropyl]-4-methylphenol[R—(R*,R*)]-2,3-dihydroxybutanedionic acid, is a muscarinic receptorantagonist and is the active ingredient found in drugs such as Detrol®(as tolterodine tartrate). In another embodiment, the first compound isthe 5-hydroxymethyl derivative of tolterodine.

The term “pharmaceutically acceptable salt” refers to a formulation of acompound that does not cause significant irritation to an organism towhich it is administered and does not abrogate the biological activityand properties of the compound. Pharmaceutical salts can be obtained byreacting a compound of the invention with inorganic acids such ashydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid, succinic acid, tartaric acid, methanesulfonic acid,ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and thelike. Pharmaceutical salts can also be obtained by reacting a compoundof the invention with a base to form a salt such as an ammonium salt, analkali metal salt, such as a sodium or a potassium salt, an alkalineearth metal salt, such as a calcium or a magnesium salt, a salt oforganic bases such as dicyclohexylamine, N-methyl-D-glucamine,tris(hydroxymethyl) methylamine, and salts thereof with amino acids suchas arginine, lysine, and the like.

Throughout the present disclosure, when a particular compound is named,it is understood that the name refers to both the free base, or freeacid, of the compound, and the pharmaceutically acceptable saltsthereof. Thus, for example, the scope of the term “tolterodine” coversboth the free base of tolterodine, i.e.,(R)-2-[3-[bis(1-methylethyl-amino]-1-phenylpropyl]-4-methylphenol[R—(R*,R*)]-2,3-dihydroxybutanedionic acid, and its variouspharmaceutically acceptable salts, for example tolterodine tartrate.

A “prodrug” refers to an agent that is converted into the parent drug invivo. Prodrugs are often useful because, in some situations, they may beeasier to administer than the parent drug. They may, for instance, bebioavailable by oral administration whereas the parent is not. Theprodrug may also have improved solubility in pharmaceutical compositionsover the parent drug, or may demonstrate increased palatability or beeasier to formulate. An example, without limitation, of a prodrug wouldbe a compound of the present invention which is administered as an ester(the “prodrug”) to facilitate transmittal across a cell membrane wherewater solubility is detrimental to mobility but which then ismetabolically hydrolyzed to the carboxylic acid, the active entity, onceinside the cell where water-solubility is beneficial. A further exampleof a prodrug might be a short peptide (polyaminoacid) bonded to an acidgroup where the peptide is metabolized to provide the active moiety.

In some embodiments, the second compound is a cholinergic agonist. Incertain embodiments, the second compound is selected from the groupconsisting of pilocarpine, cevimeline, and amifostine (the latter agentknown chemically as 2-[(3-aminopropyl)amino]ethanethiol dihydrogenphosphate (ester)), or a pharmaceutically acceptable salt or prodrugthereof. In further embodiments, the second compound is pilocarpine, ora pharmaceutically acceptable salt or prodrug thereof. In otherembodiments, the second compound is cevimeline, or a pharmaceuticallyacceptable salt or prodrug thereof.

In some embodiments, the second compound is a compound of Formula II

or a pharmaceutically acceptable salt or prodrug thereof, wherein

R₁-R₉ are each independently selected from the group consisting ofhydrogen, alkyl, nitro, amino, cyano, hydroxy, alkoxy, carboxylate, andamide.

In some embodiments, R₁ and R₂ are each independently selected from thegroup consisting of hydrogen, alkyl, hydroxy, and alkoxy. In certainembodiments, R₁ and R₂ are each independently an alkyl. In furtherembodiments, R₁ and R₂ are each independently selected from the groupconsisting of methyl, ethyl, propyl, n-butyl, isobutyl, and tert-butyl.In other embodiments, R₁ and R₂ are each independently methyl.

In some embodiments, R₃-R₉ are each independently selected from thegroup consisting of hydrogen, alkyl, hydroxy, and alkoxy. In certainembodiments, R₃-R₉ are each independently a hydrogen.

In another aspect, the present invention relates to a pharmaceuticalcomposition comprising a therapeutically effective amount of a firstcompound and a therapeutically effective amount of a second compound,wherein the first compound is an antimuscarinic or an anticholinergicagent, as described above, and the second compound relievesconstipation.

In certain embodiments, the second compound is selected from the groupconsisting of a stool softener, a laxative, a fiber treatment, and a5HT₄ receptor partial agonist. In some embodiments, the second compoundis selected from the group consisting of bisacodyl,carboxymethylcellulose, casanthranol, cascara sagrada, castor oil,danthron, dehydrocholic acid, docusate calcium, docusate sodium,glycerin, lactulose, magnesium citrate, magnesium hydroxide, magnesiumoxide, magnesium sulfate, malt soup extract, methylcellulose, milk ofmagnesia, mineral oil, mucilloid, polycarbophil, polyethylene glycol3350, poloxamer 188, psyllium, psyllium hydrophilic, senna, sennosides,and sodium phosphate.

In certain embodiments, the second compound is a compound of Formula III

or a pharmaceutically acceptable salt or prodrug thereof, wherein

R₁-R₉ are each independently selected from the group consisting ofhydrogen, alkyl, nitro, amino, cyano, hydroxy, alkoxy, carboxylate, andamide, and

m is selected from 1, 2, and 3.

In some embodiments, R₁ is selected from the group consisting ofhydrogen, alkyl, hydroxy, and alkoxy. In certain embodiments, R₁ is ahydroxy or an alkoxy. In further embodiments, R₁ is selected from thegroup consisting of hydroxy, methoxy, ethoxy, propoxy, n-butoxy,isobutoxy, and tert-butoxy. In other embodiments, R₁ is methoxy.

In some embodiments, each R₂ and R₃-R₉ are each independently selectedfrom the group consisting of hydrogen, alkyl, hydroxy, and alkoxy. Incertain embodiments, each R₂ and R₃-R₉ are each independently ahydrogen.

In some embodiments, R₉ is selected from the group consisting ofhydrogen, alkyl, hydroxy, and alkoxy. In certain embodiments, R₉ is analkyl. In further embodiments, R₉ is selected from the group consistingof methyl, ethyl, propyl, n-butyl, isobutyl, tert-butyl, pentyl, hexyl,heptyl, and octyl. In other embodiments, R₉ is n-pentyl.

In certain embodiments, the second compound is tegaserod, or apharmaceutically acceptable salt or prodrug thereof. In some of theseembodiments, the pharmaceutically acceptable salt of tegaserod isselected from the group consisting of the nitrate, lactate, succinate,sulphate, mesylate, esylate, and hydrogen sulfate salts. However, othersalts of tegaserod are also within the scope of the present invention.

Throughout the present disclosure, when a particular compound ismentioned by name, for example, oxybutynin, tolterodine, pilocarpine,cevimeline, or tegaserod, it is understood that the scope of the presentdisclosure encompasses pharmaceutically acceptable salts, esters,amides, or prodrugs of the named compound. Also, if the named compoundcomprises a chiral center, the scope of the present disclosure alsoincludes compositions comprising the racemic mixture of the twoenantiomers, as well as compositions comprising each enantiomerindividually substantially free of the other enantiomer. Thus, forexample, contemplated herein is a composition comprising the Senantiomer substantially free of the R enantiomer, or a compositioncomprising the R enantiomer substantially free of the S enantiomer. By“substantially free” it is meant that the composition comprises lessthan 10%, or less than 8%, or less than 5%, or less than 3%, or lessthan 1% of the minor enantiomer. If the named compound comprises morethan one chiral center, the scope of the present disclosure alsoincludes compositions comprising a mixture of the various diastereomers,as well as compositions comprising each diastereomer substantially freeof the other diastereomers. Thus, for example, commercially availableoxybutynin is a racemic mixture comprising two separate enantiomers. Therecitation of “oxybutynin” throughout this disclosure includescompositions that comprise the racemic mixture of oxybutynin, thecompositions that comprise the (+) enantiomer substantially free of the(−) enantiomer, and the compositions that comprise the (−) enantiomersubstantially free of the (+) enantiomer. Further, for example,commercially available pilocarpine, which is a naturally occurringalkaloid, comprises two stereocenters. The scope of the presentinvention includes pharmaceutical compositions comprising all fourdiastereomers, pharmaceutical compositions comprising the racemicmixture of R,R and S,S isomers, pharmaceutical compositions comprisingthe racemic mixture of R,S and S,R isomers, pharmaceutical compositionscomprising the R,R enantiomer substantially free of the otherdiastereomers, pharmaceutical compositions comprising the S,S enantiomersubstantially free of the other diastereomers, pharmaceuticalcompositions comprising the R,S enantiomer substantially free of theother diastereomers, and pharmaceutical compositions comprising the S,Renantiomer substantially free of the other diastereomers.

In yet another aspect, the present invention relates to a pharmaceuticalcomposition comprising a therapeutically effective amount of a firstcompound, a therapeutically effective amount of a second compound, and atherapeutically effective amount of a third compound, wherein the firstcompound is an antimuscarinic or an anticholinergic agent, as describedabove, the second compound causes stimulation of salivary glands, asdescribed above, and the third compound relieves constipation, asdescribed above.

In certain embodiments, the present invention relates to apharmaceutical composition comprising oxybutynin and pilocarpine. Inother embodiments, the present invention relates to a pharmaceuticalcomposition comprising tolterodine and pilocarpine. In yet otherembodiments, the present invention relates to a pharmaceuticalcomposition comprising trospium and pilocarpine. In some embodiments,the present invention relates to a pharmaceutical composition comprisingsolifenacin and pilocarpine. In further embodiments, the presentinvention relates to a pharmaceutical composition comprising darifenacinand pilocarpine. In yet other embodiments, the present invention relatesto a pharmaceutical composition comprising fesoterodine and pilocarpine.In other embodiments, the present invention relates to a pharmaceuticalcomposition comprising oxybutynin and cevimeline. In other embodiments,the present invention relates to a pharmaceutical composition comprisingtolterodine and cevimeline.

In certain embodiments disclosed herein, an individual is given apharmaceutical composition comprising a combination of two or morecompounds to treat overactive bladder. In some of these embodiments,each compound is a separate chemical entity. However, in otherembodiments, the two compounds are joined together by a chemicallinkage, such as a covalent bond, so that the two different compoundsform separate parts of the same molecule. The chemical linkage isselected such that after entry into the body, the linkage is broken,such as by enzymatic action, acid hydrolysis, base hydrolysis, or thelike, and the two separate compounds are then formed.

In other embodiments, the chemical linkage is selected such that it isnot broken under physiological conditions and is impervious to enzymaticattack. In these embodiments, the two parts of the compound remainintact in the patient's body. By “not broken” and “impervious” it ismeant that the half-life of the chemical reaction leading to thebreaking of the bond between the two parts of the molecule is longerthan the pharmacological half-life of the joint compound, that is, thejoint compound is excreted or metabolized faster than the bond betweenthe two parts is broken.

Thus, in another aspect, the present invention relates to syntheticroutes to novel molecules in which oxybutynin, tolterodine, trospium,solifenacin, and darifenacin is linked by a flexible linker to apilocarpine moiety or other salivary gland stimulants.

The compounds useful for the compositions and methods described hereinmay be used in various formulations. Certain formulations affect therate at which the compound enters the blood stream of the patient. Thus,some formulations are immediate release formulations while otherformulations are delayed release, sustained release, or extended releaseformulations.

Thus, in some embodiments, the first compound is in immediateformulation, while in other embodiments the first compound is in delayedrelease formulation, and in yet other embodiments the first compound isin sustained release formulation, and in further embodiments the firstcompound is in extended release formulation. In some embodiments, thesecond compound is in immediate release formulation, while in otherembodiments the second compound is in delayed release formulation, andin yet other embodiments the second compound is in sustained releaseformulation, and in further embodiments the second compound is inextended release formulation. In some embodiments, the third compound isin immediate release formulation, while in other embodiments the thirdcompound is in delayed release formulation, and in yet other embodimentsthe third compound is in sustained release formulation, and in furtherembodiments the third compound is in extended release formulation.

The compositions described herein are particularly useful in alleviatingthe major side effects in the treatment of OAB, namely dry mouth and/orconstipation, improving tolerability, and enhancing patient compliancewhile increasing the patient's quality of life.

In another aspect, the present invention relates to a method of treatinga patient comprising administering to a patient in need thereof atherapeutically effective amount of a first compound and atherapeutically effective amount of a second compound, wherein the firstcompound is an antimuscarinic or an anticholinergic agent, as describedabove, and the second compound causes stimulation of salivary glands, asdescribed above.

A patient in need of the treatment methods disclosed herein may be apatient who suffers from overactive bladder. The patient may also be onewho finds current therapies for overactive bladder uncomfortable and/orthe side effects of the therapy, such as the dry mouth or constipation,intolerable enough so as to require adjunct therapy to alleviate theside effects. The patient may also be one who is consideringdiscontinuing therapy for overactive bladder due to the side effects ofthe therapy. In some embodiments, a patient who is recently diagnosedwith overactive bladder but yet has not been treated therefore is apatient in need of the treatment methods and compositions disclosedherein. In these embodiments, the patient begins the therapy using themethods and combinations disclosed herein so that the patient does notexperience any of the side effects, or experience the side effects to alesser degree.

In some embodiments, the patient may be suffering from overactivebladder, urge, stress, and mixed incontinence.

In some embodiments the first compound and the second compound areadministered more or less simultaneously. In other embodiments the firstcompound is administered prior to the second compound. In yet otherembodiments, the first compound is administered subsequent to the secondcompound.

In another aspect, the present invention relates to a method of treatinga patient comprising identifying a patient suffering from overactivebladder, and administering to the patient a therapeutically effectiveamount of a first compound and a therapeutically effective amount of asecond compound, wherein the first compound is an antimuscarinic or ananticholinergic agent, as described above, and second compound relievesconstipation, as described above.

In some embodiments, the patient may be suffering from overactivebladder, urge, stress, and mixed incontinence.

In yet another aspect, the present invention relates to a method oftreating a patient comprising administering to a patient in need thereofa therapeutically effective amount of a first compound, atherapeutically effective amount of a second compound, and atherapeutically effective amount of a third compound, wherein the firstcompound is an antimuscarinic or an anticholinergic agent, as describedabove, the second compound causes stimulation of salivary glands, asdescribed above, and the third compound relieves constipation, asdescribed above.

In some embodiments, the patient may be suffering from overactivebladder, urge, stress, and mixed incontinence.

In some embodiments in the above methods, the first compound and thesecond compound are administered more or less simultaneously. In otherembodiments the first compound is administered prior to the secondcompound. In yet other embodiments, the first compound is administeredsubsequent to the second compound.

In certain embodiments in the above methods, the first compound and thesecond compound are administered individually. In other embodiments, thefirst compound and the second compound may be covalently linked to eachother such that they form a single chemical entity. The single chemicalentity is then digested and is metabolized into two separatephysiologically active chemical entities, one of which is the firstcompound and the other one is the second compound. Both chemicalentities once metabolized exert their therapeutic effect independentlyor synergistically. In further embodiments the bond between the twoparts of the compound is not broken and each part of the joint moleculeexerts its therapeutic effect independently, without the necessity ofthe cleavage of linker between the two parts.

It should be noted that simply taking commercially available pilocarpineHCl, e.g., Salagen® tablets, or any other salivary gland stimulants inconjunction with an OAB drug is not effective to alleviate the dry mouthside effect. Certain effective treatments match the pharmacokineticsprofile of each salivary gland stimulants, such as pilocarpine,cevimeline HCl, and amifostine, with the pharmacokinetics profiles ofthe OAB agents, for example oxybutynin, tolterodine, solifenacin,darifenacin, trospium, and other approved agents or in development.

Therefore, in certain embodiments in the above methods, the first andsecond compounds are administered such that the peak plasmaconcentration for the first compound occurs at nearly the same timeafter administration as the peak plasma concentration for the secondcompound. Thus, the two compounds may be administered simultaneously,but be formulated such that the delay in their release causes the twopeak plasma concentrations to occur at nearly the same time. In otherembodiments, one compound is administered at a time interval after theother compound in order to ensure that the peak plasma concentrationsoccur at nearly the same time.

In other embodiments in the above methods, the first and secondcompounds are administered such that the time point at which the lowestsaliva flow occurs because of the action of the first compound nearlycorresponds to the time point at which the highest saliva flow occursbecause of the action of the second compound. Thus, the two compoundsmay be administered simultaneously, but be formulated such that thedelay in their release causes the peak saliva flow time point for thesecond compound to occur at nearly the same time as the lowest salivaflow time point for the first compound. In other embodiments, onecompound is administered at a time interval after the other compound inorder to ensure that peak and trough saliva flow time points match.

In some embodiments in the above methods, the first and second compoundsare administered such that the ratio of their plasma concentrations, ata given point in point following their administration, is apredetermined value. Those of ordinary skill in the art recognize thatthe ratio of plasma concentrations is not necessarily the same as theratio of the amount of compound administered. Compounds are digesteddifferently in the gut, pass the gut wall differently, and have adifferent rate of first-pass metabolism in the liver. Furthermore, theclearance rate by the kidney is different for various compounds. Thus,for example, even if two compounds are administered in equivalent molaramounts, their plasma concentrations at a point in time after theadministration may be significantly different. The methods disclosedherein take into account the pharmacokinetics of drug intake andmetabolism, such that the ratio of the two compounds at the time ofadministration is adjusted so that the two compounds would have apredetermined concentration ratio in the plasma.

In yet other embodiments in the above methods, the first and secondcompounds are administered such that the time point for the maximumtherapeutic effect of the compound that stimulates saliva flow matchesthe time point for the maximum side effect of the OAB therapeuticcompound. Thus, the two compounds may be administered simultaneously,but be formulated such that the delay in their release causes themaximum therapeutic effect of the second compound to occur at nearly thesame time as the maximum side effect of the first compound. In otherembodiments, one compound is administered at a time interval after theother compound in order to ensure that the maximum therapeutic effect ofthe second compound to occur at nearly the same time as the maximum sideeffect of the first compound.

In some embodiments the dosage form is designed as sustained release ofone agent combined with either sustained release or immediate release ofthe second agent to ensure that the peak plasma concentrations occur atnearly the same time. Further the dosage from can be designed based onthe pharmacokinetics profiles where the peak plasma concentration of onecompound, for example the salivary gland stimulant agent, e.g.,pilocarpine, corresponds to maximum amount of mouth dryness caused bythe OAB drug, for example oxybutynin.

Thus, some of the pharmaceutical compositions contemplated for use inthe methods disclosed herein include, but are not limited to:

immediate release oxybutynin, tolterodine, solifenacin, darifenacin,trospium, or fesoterodine, in combination with pilocarpine andtegaserod;

delayed (whether sustained or extended) release oxybutynin and delayed(whether sustained or extended) release pilocarpine;

delayed (whether sustained or extended) release oxybutynin and delayed(whether sustained or extended) release pilocarpine and sustainedrelease tegaserod;

immediate release oxybutynin, tolterodine, solifenacin, darifenacin,trospium, or fesoterodine, and delayed (whether sustained or extended)formulation of pilocarpine and tegaserod;

delayed (whether sustained or extended) release oxybutynin, tolterodine,solifenacin, darifenacin, trospium, or fesoterodine, and delayed(whether sustained or extended) release of pilocarpine and sustainedrelease tegaserod;

delayed (whether sustained or extended) release oxybutynin, tolterodine,solifenacin, darifenacin, trospium, or fesoterodine, and delayed(whether sustained or extended) formulation of pilocarpine and immediaterelease formulation of tegaserod.

Without being bound by a particular theory, the improved treatmentdisclosed here of OAB in addressing the dry mouth and constipation isbased on a mechanistic approach working at the receptor level, i.e., theadverse effect of these M2/M3 muscarinic antagonists is counteracted ornegated with cholinergic agents that work in the opposite direction butin concert with the intended therapy.

Besides reducing the adverse side effects experienced by those beingtreated for overactive bladder, the methods and compositions disclosedherein have additional advantages. Currently, the dose of treatmentdrugs, such as oxybutynin, is limited because of the side effects. Somepatients who suffer from overactive bladder cannot tolerate dosages thatprovide adequate therapy because of the adverse side effects, e.g., drymouth. These patients continue to suffer from overactive bladder eventhough they take their medications, solely because the medication is notadministered at an effective dose. By lowering the side effects usingthe methods and compositions disclosed herein, the patient can beprescribed to take treatment drugs, such as oxybutynin, at higher doses.These higher doses result in having a less active bladder and alsoresult in an increase in intrinsic bladder capacity.

Thus, in another aspect, the present invention relates to a method ofincreasing intrinsic bladder capacity, comprising administering to apatient in need thereof a therapeutically effective amount of a firstcompound and a therapeutically effective amount of a second compound,wherein the first compound is an antimuscarinic or an anticholinergicagent, as described above, and the second compound causes stimulation ofsalivary glands, as described above.

In another aspect, the present invention relates to a method ofincreasing intrinsic bladder capacity, comprising administering to apatient in need thereof a therapeutically effective amount of a firstcompound and a therapeutically effective amount of a second compound,wherein the first compound is an antimuscarinic or an anticholinergicagent, as described above, and the second compound relievesconstipation, as described above.

In another aspect, the present invention relates to a method ofincreasing intrinsic bladder capacity, comprising administering to apatient in need thereof a therapeutically effective amount of a firstcompound, a therapeutically effective amount of a second compound, and atherapeutically effective amount of a third compound, wherein the firstcompound is an antimuscarinic or an anticholinergic agent, as describedabove, the second compound causes stimulation of salivary glands, asdescribed above, and the third compound relieves constipation, asdescribed above.

In another aspect, the invention relates to a pharmaceutical compositioncomprising a combination of:

an antimuscarinic or an anticholinergic agent, as described herein, anda compound that causes stimulation of salivary glands, as describedherein;

an antimuscarinic or an anticholinergic agent, as described herein, anda compound that relieves constipation, as described herein; or

an antimuscarinic or an anticholinergic agent, as described herein, acompound that causes stimulation of salivary glands, as describedherein, and a compound that relieves constipation, as described herein;and

a physiologically acceptable carrier, diluent, or excipient, or acombination thereof.

The term “pharmaceutical composition” refers to a mixture of a compoundof the invention with other chemical components, such as diluents,lubricants, bulking agents, desentegrant or carriers. The pharmaceuticalcomposition facilitates administration of the compound to an organism.Multiple techniques of administering a compound exist in the artincluding, but not limited to, oral, injection, inhalation, aerosol,parenteral, and topical administration. Pharmaceutical compositions canalso be obtained by reacting compounds with inorganic or organic acidssuch as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid, methanesulfonic acid, ethanesulfonic acid,p-toluenesulfonic acid, salicylic acid and the like.

The term “carrier” defines a chemical compound that facilitates theincorporation of a compound into cells or tissues. For example dimethylsulfoxide (DMSO) is a commonly utilized carrier as it facilitates theuptake of many organic compounds into the cells or tissues of anorganism.

The term “diluent” defines chemical compounds diluted in water that willdissolve the compound of interest as well as stabilize the biologicallyactive form of the compound. Salts dissolved in buffered solutions areutilized as diluents in the art. One commonly used buffered solution isphosphate buffered saline because it mimics the salt conditions of humanblood. Since buffer salts can control the pH of a solution at lowconcentrations, a buffered diluent rarely modifies the biologicalactivity of a compound.

In certain embodiments, the same substance can act as a carrier,diluent, or excipient, or have any of the two roles, or have all threeroles. Thus, a single additive to the pharmaceutical composition canhave multiple functions.

The term “physiologically acceptable” defines a carrier or diluent thatdoes not abrogate the biological activity and properties of thecompound.

The pharmaceutical compositions described herein can be administered toa human patient per se, or in pharmaceutical compositions where they aremixed with other active ingredients, as in combination therapy, orsuitable carriers or excipient(s). Techniques for formulation andadministration of the compounds of the instant application may be foundin “Remington's Pharmaceutical Sciences,” Mack Publishing Co., Easton,Pa., 18th edition, 1990.

Suitable routes of administration may, for example, include oral,transdermal, rectal, transmucosal, or intestinal administration;parenteral delivery, including intramuscular, subcutaneous, intravenous,intramedullary injections, as well as inhalation, intrathecal, directintraventricular, intraperitoneal, intranasal, or intraocularinjections.

Alternately, one may administer the compound in a local rather thansystemic manner, for example, via injection of the compound directly inthe renal or cardiac area, often in a depot or sustained, extended, ordelayed release formulation. In addition, one may administer thecomposition by transdermal approach.

The pharmaceutical compositions of the present invention may bemanufactured in a manner that is itself known, e.g., by means ofconventional mixing, dissolving, granulating, dragee-making, levigating,emulsifying, encapsulating, entrapping or tabletting processes.

Pharmaceutical compositions for use in accordance with the presentinvention thus may be formulated in conventional manner using one ormore physiologically acceptable carriers comprising excipients andauxiliaries which facilitate processing of the active compounds intopreparations which can be used pharmaceutically. Proper formulation isdependent upon the route of administration chosen and desiredpharmacokinetics profiles of each component of combination therapy. Anyof the well-known techniques, carriers, and excipients may be used assuitable and as understood in the art; e.g., in Remington'sPharmaceutical Sciences, above.

For injection, the agents of the invention may be formulated in aqueoussolutions, preferably in physiologically compatible buffers such asHanks's solution, Ringer's solution, or physiological saline buffer. Fortransmucosal administration, penetrants appropriate to the barrier to bepermeated are used in the formulation. Such penetrants are generallyknown in the art.

For oral administration, the compounds can be formulated readily bycombining the active compounds with pharmaceutically acceptable carrierswell known in the art. Such carriers enable the compounds of theinvention to be formulated as tablets, pills, dragees, capsules,liquids, gels, syrups, slurries, suspensions and the like, for oralingestion by a patient to be treated. Pharmaceutical preparations fororal use can be obtained by mixing one or more solid excipient withpharmaceutical combination of the invention, optionally grinding theresulting mixture, and processing the mixture of granules, after addingsuitable auxiliaries, if desired, to obtain tablets or dragee cores.Suitable excipients are, in particular, fillers such as sugars,including lactose, sucrose, mannitol, or sorbitol; cellulosepreparations such as, for example, maize starch, wheat starch, ricestarch, potato starch, gelatin, gum tragacanth, methyl cellulose,hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and/orpolyvinylpyrrolidone (PVP). If desired, disintegrating agents may beadded, such as the cross-linked polyvinyl pyrrolidone, agar, or alginicacid or a salt thereof such as sodium alginate.

Dragee cores are provided with suitable coatings. For this purpose,concentrated sugar solutions may be used, which may optionally containgum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethyleneglycol, and/or titanium dioxide, lacquer solutions, and suitable organicsolvents or solvent mixtures. Dyestuffs or pigments may be added to thetablets or dragee coatings for identification or to characterizedifferent combinations of active compound doses.

Pharmaceutical preparations that can be used orally include push-fitcapsules made of gelatin, as well as soft, sealed capsules made ofgelatin and a plasticizer, such as glycerol or sorbitol. The push-fitcapsules can contain the active ingredients in admixture with fillersuch as lactose, binders such as starches, and/or lubricants such astalc or magnesium stearate and, optionally, stabilizers. In softcapsules, the active compounds may be dissolved or suspended in suitableliquids, such as fatty oils, liquid paraffin, or liquid polyethyleneglycols. In addition, stabilizers may be added. All formulations fororal administration should be in dosages suitable for suchadministration.

For buccal administration, the compositions may take the form of tabletsor lozenges formulated in conventional manner.

The compounds may also be formulated in rectal compositions such assuppositories or retention enemas.

Many of the compounds used in the pharmaceutical combinations of theinvention may be provided as salts with pharmaceutically compatiblecounterions. Pharmaceutically compatible salts may be formed with manyacids, including but not limited to hydrochloric, sulfuric, acetic,lactic, tartaric, malic, succinic, and the like. Salts tend to be moresoluble in aqueous or other protonic solvents than are the correspondingfree acids or base forms.

Pharmaceutical compositions suitable for use in the present inventioninclude compositions where the active ingredients are contained in anamount effective to achieve its intended purpose. More specifically, atherapeutically effective amount means an amount of compound effectiveto prevent, alleviate or ameliorate symptoms of disease or prolong thesurvival of the subject being treated.

Typically, the dose range of the composition administered to the patientcan be from about 0.5 to 1000 mg/kg of the patient's body weight. Thedosage may be a single one or a series of two or more given in thecourse of one or more days, as is needed by the patient. Note that foralmost all of the specific compounds mentioned in the presentdisclosure, human dosages for treatment of at least some condition havebeen established. For example, for oxybutynin, tolterodine, solifenacin,darifenacin, trospium, fesoterodine the preferred dosage is between 0.1mg to 50 mg, and the more preferred dosage is between 1 mg to 30 mg.Other dose ranges include between 10 to 50 mg, between 20 to 50 mg,between 30 to 50 mg, between 40 to 50 mg, between 20 to 40 mg, between10 to 20 mg, between 10 to 30 mg, between 20 to 30 mg, and between 30 to40 mg. The dose may also be at 10 mg, 20 mg, 30 mg, 40 mg, or 50 mg. Forpilocarpine, the preferred dosage is between 0.1 mg to 50 mg, and themore preferred dosage is between 1 mg to 30 mg. Other dose rangesinclude between 10 to 50 mg, between 20 to 50 mg, between 30 to 50 mg,between 40 to 50 mg, between 20 to 40 mg, and between 30 to 40 mg. Thedose may also be at 10 mg, 20 mg, 30 mg, 40 mg, or 50 mg. For tegaserod,the preferred dosage is between 0.05 mg to 50 mg, and the more preferreddosage is between 0.5 mg to 2 mg. Other dose ranges include between 10to 50 mg, between 20 to 50 mg, between 30 to 50 mg, between 40 to 50 mg,between 20 to 40 mg, between 30 to 40 mg, between 0.5 to 1 mg, andbetween 1 to 2 mg. The dose may also be at 0.5 mg, 1 mg, 1.5 mg, and 2mg.

Although the exact dosage can be determined on a drug-by-drug basis, inmost cases, some generalizations regarding the dosage can be made. Thedaily dosage regimen for an adult human patient may be, for example, anoral dose of between 0.001 mg and 1000 mg of each ingredient, preferablybetween 0.01 mg and 500 mg, for example 1 to 200 mg or each ingredientof the pharmaceutical compositions of the present invention or apharmaceutically acceptable salt thereof calculated as the free base orfree acid, the composition being administered 1 to 4 times per day orper week. Alternatively the compositions of the invention may beadministered by continuous such as sustained, delayed, or extendedrelease, preferably at a dose of each ingredient up to 500 mg per day.Thus, the total daily dosage by oral administration of each ingredientwill typically be in the range 0.1 mg to 2000 mg. Suitably the compoundswill be administered for a period of continuous therapy, for example fora day, a week or more, or for months or years.

In cases of local administration or selective uptake, the effectivelocal concentration of the drug may not be related to plasmaconcentration.

The amount of composition administered will, of course, be dependent onthe subject being treated, on the subject's weight, the severity of theaffliction, the manner of administration and the judgment of theprescribing physician.

It will be understood by those of skill in the art that numerous andvarious modifications can be made without departing from the spirit ofthe present invention. Therefore, it should be clearly understood thatthe forms of the present invention are illustrative only and are notintended to limit the scope of the present invention.

EXAMPLES

The examples below are non-limiting and are merely representative ofvarious aspects of the invention.

Example 1 Combination of an OAB Drug and a Salivary Gland Stimulant forthe Treatment of Individual with Overactive Bladder

An individual with overactive bladder is identified. The individual isgiven 5 mg of oxybutynin two to four times a day in addition to 5 mg ofpilocarpine two or three times a day. If the individual continues tocomplain about dry mouth, the dose of pilocarpine is increased to 10 mgtwo or three times a day. The dose can be increased up to 20 mg, or 50mg, if needed. Each dose of oxybutynin can be increased to 10, 15, 20,or 30 mg.

Example 2 Combination of an OAB Drug and a Tegaserod for the Treatmentof Individual with Overactive Bladder

An individual with overactive bladder is identified. The individual isgiven 5 mg of oxybutynin two to four times a day in addition to 2 mg oftegaserod twice a day. If the individual continues to complain aboutconstipation, the dose of tegaserod is increased to 6 mg twice a day.The dose can be increased up to 12 mg, 20 mg, or 50 mg, if needed. Thedose of oxybutynin can be increased to 10, 15, 20, or 30 mg.

Example 3 Clinical Study Protocol Synopsis

A study is conducted to evaluate the effect of oxybutynin andpilocarpine, alone and in combination versus placebo on salivary outputin healthy volunteers. The objectives of the study are to determinesalivary flow and degree of dry mouth after oral administration ofoxybutynin and pilocarpine, alone and in combination, vs. placebo, andto determine the effect of oxybutynin and pilocarpine, alone and incombination, on urine volume/void and vital signs.

At each treatment period, following an overnight fast, subjects enterthe clinic and after baseline measurements have been made, they arerandomized to one of four medications

-   -   Oxybutynin (5 mg) followed 30 minutes later by placebo    -   Pilocarpine (5 mg) followed 30 minutes later by placebo    -   Placebo followed 30 minutes later by placebo    -   Oxybutynin (5 mg) followed 30 minutes by pilocarpine (5 mg)

The following measurements are made just prior to and at frequentintervals for up to 6 hours post dose:

-   -   Salivary flow is determined by chewing Parafilm for 2 minutes    -   Dry mouth is determined by VAS    -   Urine volume/void and frequency over 6 hours post dose is        measured    -   Blood samples are taken for pharmacokinetics at pre-dose, and at        0.5, 1, 2, 3, 4, and 6 hours post dose    -   Food and water intake are standardized over the 6 hour period

The study is a double blind, randomized, placebo-controlled, with 4sequences (4 doses over 4 weeks) with the drugs being administeredorally as a single dose. There is a One-week washout between study days.The study population is chosen as follows:

-   -   Healthy volunteers    -   12 subjects    -   ≧18 years males or non-pregnant females    -   Weight 18-28 BMI    -   No known allergy to antimuscarinic agents    -   No previous history of glaucoma, urinary retention, cardiac        arrhythmias    -   No OTC medications, nutriceuticals or vitamins within 10 days of        study enrollment and throughout the study

Assessments (except for urine output) is performed at: 0.5 hr and within10 minutes pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, and 6 hourspost dose. The following are assessed:

-   -   1) Stimulated salivary flow    -   2) Dry mouth (VAS)    -   3) Urine volume/void over 6 hours post dose    -   4) Pharmacokinetics of oxybutynin and pilocarpine

The standard safety precautions, such as physical exam, medical history,con-meds, ECG, hematology, clinical chemistry, urinalysis performed atscreening and study termination, urine drug/alcohol screening atpre-dose for each period, vital signs (HR and BP) at: pre-dose, and at30 min intervals for 6 hours, and an awareness of adverse eventsthroughout and between study period, are taken.

Example 4 Case Study for a Combination of Oxybutynin and Pilocarpine

In this study, the effect of oxybutynin, pilocarpine, the combination ofthe two, and placebo was measured in six separate, yet identical,studies in a single individual.

Effect of Oxybutynin—A healthy human subject was given a 5 mg dose ofoxybutynin HCl and the amount of salivation was measured with time overan 8 hour period. As shown in FIG. 1 (♦, diamond), the amount of salivaflow collected over 2 minutes periods decreased after dosing ofoxybutynin and the saliva flow remained low after 3 hrs. The amount ofsaliva flow started increasing after 3 hrs and continued increasingreaching the pre-dose level after 8 hrs post-dosing. The data generatedin this study is consistent with the literature data.

Effect of Pilocarpine—In a separate human study the effect ofpilocarpine HCl was evaluated in a healthy human subject to ensure thatpilocarpine indeed increases salivary gland flow. This was demonstratedas shown in FIG. 1 (▪, square). The amount of saliva collected over 2minute periods increased sharply after dosing and the saliva flowstarted decreasing after the peak observed at half an hour. The decreasein saliva flow continued until it reached about the normal saliva flowand pre-dosing level after about 5 hrs.

Effect of Placebo—In the third leg of the human study, the effect ofplacebo was evaluated. Since this was an unblinded trial, the salivaryflow was measured by not taking any medication or a true placebo but thesame protocol was followed as in the other studies. As shown in the FIG.1 (▴, triangle), the variation in salivary flow with time is minimal andthe average salivary flow is about 2 g/2 min, consistent with thepublished literature.

Effect of Combination of Oxybutynin and Pilocarpine—In a separate humanstudy, the combination of oxybutynin and pilocarpine was administered toa healthy human subject. To the subject 5 mg of oxybutynin followed by 5mg of pilocarpine after 30 min of dosing was administered. Saliva flowwas measured as before. Results are shown in FIG. 1 (, circle).

As shown in FIG. 1, the decreased in salivary flow caused by oxybutyninwas compensated well by the increase in salivary flow induced bypilocarpine. As a result, the amount of salivary flow remained about thesame as the pre-dose level. FIG. 1 further shows that the amount ofsalivary flow measured for the combination study was similar to that ofthe placebo study. Therefore, administration of 5 mg pilocarpine at halfhour after the administration of 5 mg of oxybutynin completelyneutralized the adverse side effect of oxybutynin.

The percentage of saliva flow deviation from baseline followingadministration of pilocarpine, oxybutynin, combination of pilocarpineand oxybutynin (with pilocarpine administered 30 min after oxybutynin),and placebo were plotted against time and are shown in FIG. 2. Thepercent deviation for the combination study, where pilocarpine wasadministered 30 min after oxybutynin, (, circle) is minimal and notsignificantly different from the baseline or the placebo (▴, triangle)suggesting that the combination approach eliminates the major sideeffect of OAB therapy.

Effect of Timing of the Administration of Pilocarpine with Respect tothe Administration of Oxybutynin—In two additional human studies, theeffect of the timing of administration of pilocarpine was measured. Inone study, the combination of oxybutynin and pilocarpine wasadministered to a healthy human subject. To the subject 5 mg ofoxybutynin and 5 mg of pilocarpine were administered simultaneously.Saliva flow was measured as before. Results are shown in FIG. 3 (▪,square). In the last study, the combination of oxybutynin andpilocarpine was administered to a healthy human subject. To the subject5 mg of oxybutynin followed by 5 mg of pilocarpine after 60 min ofdosing was administered. Saliva flow was measured as before. Results areshown in FIG. 3 (♦, diamond).

FIG. 3 shows the effect of time delay for the administration ofpilocarpine. All studies are compared to placebo (▴, triangle). Whenoxybutynin and pilocarpine are administered at the same time (▪,square), there is an initial large increase in saliva flow, whichreaches a maximum at about t=30 min to less than about t=60 min, butthen drops to normal (placebo) levels at about t=1 hr and stays at thislevel. When pilocarpine is administered 60 minutes after oxybutynin (♦,diamond), there is a precipitous drop in saliva flow which last untilabout t=1 hr, after which there is a large increase in saliva flow, witha maximum occurring at about t=3 hrs. The saliva flow returns to normal(placebo) at about t=5 hrs. However, when pilocarpine is administered 30minutes after oxybutynin (, circle), there is a small drop in salivaflow with a minimum at about t=30 min, but it returns to normal(placebo) within one hour.

Effect of Dose Ratio Between Oxybutynin and Pilocarpine—In thisexperiment the results of two separate dose ratios between oxybutyninand pilocarpine were compared with the results of placebo andadministration of oxybutynin alone. In one experiment, 5 mg ofoxybutynin was administered to a healthy individual and saliva flow wasmeasured for 8 hours. The results are shown in FIG. 4 (♦, diamond).Using a similar protocol, 5 mg of oxybutynin was administered to ahealthy individual at t=0, followed by 5 mg of pilocarpine at t=30 min.The results are shown in FIG. 4 (, circle). Similarly, 10 mg ofoxybutynin was administered to a healthy individual at t=0, followed by5 mg of pilocarpine at t=30 min. The results are shown in FIG. 4 (-,dash). Finally, the results were compared with the administration ofplacebo (FIG. 4 (▴, triangle)).

The results shown in FIG. 4 suggest that increasing oxybutynin from 5 to10 mg lead to decrease in salivation. The increase in ratio from 1:1 to2:1 perturbs the balance between the decreased salivation by oxybutyninand increased salivation by pilocarpine, respectively. It is noted thatthe saliva flow for the 2:1 oxybutynin:pilocarpine ratio is similar tothat of the 5 mg oxybutynin alone, suggesting that the amount of 5 mgpilocarpine in this experiment is not sufficient to compensate thedecrease in saliva flow caused by the increase in amount of oxybutyninfrom 5 to 10 mg. Therefore, an effective dose ratio for the combinationoxybutynin and pilocarpine is when 5 mg of each is administered to apatient.

Plasma Concentration of Oxybutynin—In a separate study, the plasmaconcentration of oxybutynin was measured in two groups of subjects: onegroup received 5 mg of oxybutynin alone and another group received 5 mgof oxybutynin followed by 5 mg pilocarpine after 30 min. The plasmaconcentrations were measured before the administration of oxybutynin andin hours 1, 2, 3, 4, and 6 after its administration. The results areshown in Tables 1 and 2, below. Table 1 shows the plasma levels ofoxybutynin after the administration of 5 mg of oxybutynin alone in aplacebo controlled, blinded, four way crossover clinical trial in 12male subjects. Table 2 presents the plasma levels of oxybutynin afterthe administration of 5 mg of oxybutynin followed by the administrationof 5 mg of pilocarpine 30 min after the administration of oxybutynin ina placebo controlled, blinded, four way crossover clinical trial in 12male subjects.

TABLE 1 Plasma Level of Oxybutynin (ng/mL) Time (Hour) After OxybutyninAdministration Subject Number 0 1 2 3 4 6 1 0.000 0.980 1.760 1.6200.869 0.786 2 0.000 5.380 2.910 2.410 1.490 1.150 3 0.000 9.840 3.8702.320 1.840 1.150 4 0.120 3.250 1.990 1.270 1.070 0.783 5 0.020 16.0009.260 3.920 4.690 1.900 6 0.000 2.600 1.400 1.230 1.140 1.330 7 0.00015.420 6.110 2.700 2.390 0.650 8 0.000 7.600 2.890 1.530 0.010 0.000 90.000 3.910 2.580 0.440 0.210 0.190 10 0.000 7.230 3.120 1.330 0.8800.190 11 0.000 4.900 1.820 0.970 0.340 0.560 12 0.000 3.200 1.520 0.7900.230 0.000 Mean 0.012 6.693 3.269 1.711 1.263 0.724 STD 0.0345974.861029 2.289476 0.969634 1.291618 0.585548

TABLE 2 Plasma Level of Oxybutynin (ng/mL) Time (Hour) After OxybutyninAdministration Subject Number 0 1 2 3 4 6 1 0.000 1.830 1.380 0.9800.977 0.740 2 0.000 5.260 2.490 1.220 1.820 1.100 3 0.000 1.720 2.1206.920 5.150 3.100 4 0.020 3.080 2.790 2.230 1.460 0.150 5 0.000 14.6006.580 2.550 5.010 1.580 6 0.000 2.750 1.690 1.280 1.020 0.000 7 0.00020.800 11.100 5.310 3.060 2.110 8 0.000 1.180 0.470 0.230 0.270 0.000 90.000 8.580 2.920 1.410 0.940 0.550 10 0.000 9.200 3.650 1.870 1.1100.340 11 0.000 7.490 1.710 1.340 0.600 0.680 12 0.000 3.480 1.520 0.9300.560 0.260 Mean 0.001538 6.228462 3.109231 2.251538 1.998231 1.277692STD 0 5.967714 2.92391 1.961773 1.67978 0.948956

As can be seen from the tables, in both groups, the plasma concentrationof oxybutynin reaches a maximum at about an hour, followed by a gradualdecline. Moreover, the plasma concentration of oxybutynin follows thesame curve for both groups. Therefore, addition of 5 mg of pilocarpinedoes not affect the plasma concentration of oxybutynin at all. Twoconclusions follow from this observation. First, pilocarpine does notaffect the absorption of oxybutynin in the gut, nor does it affect thefirst-pass metabolism of pilocarpine in the liver. Second, pilocarpinedoes not affect the binding ability of oxybutynin, since theconcentration of free oxybutynin in the plasma remains the same betweenthe two groups. Further, the presence of pilocarpine in the combinationdoes not interfere with the pharmacokinetics of oxybutynin. Thus, theantimuscarinic activity of oxybutynin responsible for therapeutic effectof oxybutynin on OAB remains unaffected.

Example 5 Case Study for a Combination of Oxybutynin and Cevimeline

In this study, the effect of oxybutynin, cevimeline, the combination ofthe two, and placebo was measured in separate studies in a singleindividual.

Effect of Oxybutynin—A healthy human subject was given a 5 mg dose ofoxybutynin HCl and the amount of salivation was measured with time overan 8 hour period. As shown in FIG. 5 (, circle), the amount of salivaflow collected over 2 minutes periods decreased after dosing and thesaliva flow remained low after 3 hrs. The amount of saliva flow startedincreasing after 3 hrs and continued increasing reaching the pre-doselevel after 8 hrs post-dosing. The data generated in this study isconsistent with the literature data.

Effect of Cevimeline—In a separate human study the effect ofadministering 30 mg of cevimeline was evaluated in a healthy humansubject to ensure that cevimeline indeed increases salivary gland flow.This was demonstrated as shown in FIG. 5 (♦, diamond). The amount ofsaliva collected over 2 minute periods increased sharply after dosingand the saliva flow started decreasing after the peak observed at closeto two hours. The decrease in saliva flow continued until it reachedabout the normal saliva flow and pre-dosing level after about 6 hrs.

Effect of Placebo—In the third leg of the human study, the effect ofplacebo was evaluated. Since this was an unblinded trial, the salivaryflow was measured by not taking any medication or a true placebo but thesame protocol was followed as in the other studies. As shown in the FIG.5 (▴, triangle), the variation in salivary flow with time is minimal andthe average salivary flow is about 2.5 g/2 min, consistent with thepublished literature.

Effect of Combination of Oxybutynin and Cevimeline—In a separate humanstudy, the combination of oxybutynin and cevimeline was administered toa healthy human subject. To the subject 5 mg of oxybutynin followedsimultaneously by 30 mg of cevimeline, with no time delay, wasadministered. Saliva flow was measured as before. Results are shown inFIG. 5 (▪, square), where the combination is referred to as THVD-102.

The results of the above experiments are also shown in the Table 3,below, which shows the data for the evaluation of the combination ofoxybutynin and cevimeline on stimulated salivary flow. FIG. 5 is agraphic illustration of the data set forth in Table 3.

TABLE 3 Agent Cevimeline Cev + Oxy Oxybutynin Placebo Oxybutynin, mg 0 55 0 Cevimeline, mg 30 30 0 0 Amount of Saliva Amount of Saliva Time (hr)Collecetd over 2 min Collecetd over 2 min −0.17 2.4808 2.862 2.22081.7143 0 2.6273 2.9442 2.4536 1.4786 0.5 2.7791 2.3742 1.8558 1.959  14.1213 2.4091 1.2308 2.0143 1.5 4.6029 3.0437 1.2326 1.9861 2 3.73142.2793 1.3548 2.0671 2.5 3.7641 2.4445 n/d* n/d 3 3.5888 2.0601 1.18291.6538 3.5 3.9316 2.5827 n/d n/d 4 3.5914 2.4358 1.5868 1.9866 5 2.60992.312 2.1475 1.8417 6 2.205 2.4915 2.0096 2.3332 8 1.7973 2.4158 2.30282.0182 *Not determined

As shown in FIG. 5, the decreased in salivary flow caused by oxybutyninwas compensated well by the increase in salivary flow induced bycevimeline. As a result, the amount of salivary flow remained about thesame as the pre-dose level. FIG. 5 further shows that the amount ofsalivary flow measured for the combination study was similar to that ofthe placebo study. Therefore, administration of 30 mg cevimelinesimultaneously with the administration of 5 mg of oxybutynin completelyneutralized the adverse side effect of oxybutynin.

Example 6 Case Study for a Combination of Tolterodine and Pilocamine

In this study, the effect of tolterodine, pilocarpine, the combinationof the two, and placebo was measured in separate, yet identical, studiesin a single individual.

Effect of Tolterodine—A healthy human subject was given a 2 mg dose oftolterodine tartrate and the amount of salivation was measured with timeover an 8 hour period. As shown in FIGS. 6 and 7 (♦, diamond), theamount of saliva flow collected over 2 minute periods decreased afterdosing and the saliva flow remained low after 3 hrs. The amount ofsaliva flow started increasing after about 4 hrs and continuedincreasing, but did not completely reach the pre-dose levels even after8 hrs post-dosing.

Effect of Pilocarpine—The effect of the administration of pilocarpineindividually has been studied and the data is shown above.

Effect of Placebo—In another leg of the human study, the effect ofplacebo was evaluated. Since this was an unblinded trial, the salivaryflow was measured by not taking any medication or a true placebo but thesame protocol was followed as in the other studies. As shown in theFIGS. 6 and 7 (, closed circle), the variation in salivary flow withtime is minimal and the average salivary flow is about 2.5 g/2 min,consistent with the published literature.

Effect of Dose Ratio Between Tolterodine and Pilocarpine—In thisexperiment the results of two separate dose ratios between tolterodineand pilocarpine were compared with the results of placebo andadministration of tolterodine alone. In one experiment, 2 mg oftolterodine was administered to a healthy individual and saliva flow wasmeasured for 8 hours. The results are shown in FIG. 6 (♦, diamond).Using a similar protocol, 2 mg of tolterodine was administered to ahealthy individual at t=0, followed by 5 mg of pilocarpine at t=30 min.The results are shown in FIG. 6 (▴, closed triangle). Similarly, 2 mg oftolterodine was administered to a healthy individual at t=0, followed by10 mg of pilocarpine at t=30 min. The results are shown in FIG. 6 (o,open circle). Finally, the results were compared with the administrationof placebo (FIG. 6 (, closed circle)). The results shown in FIG. 6suggest that increasing pilocarpine from 5 to 10 mg lead to increase insalivation. The decrease in ratio from 2:5 to 2:10(tolterodine:pilocarpine) restores the balance between the decreasedsalivation by tolterodine and increased salivation by pilocarpine,respectively. It is noted that the saliva flow for the 2:5tolterodine:pilocarpine ratio is similar to that of the 2 mg tolterodinealone, suggesting that the amount of 5 mg pilocarpine in this experimentis not sufficient to compensate the decrease in saliva flow caused by 2mg of tolterodine. Therefore, an effective dose ratio for thecombination oxybutynin and pilocarpine is when 2 mg of tolterodine iscombined with 10 mg of pilocarpine.

Effect of Combination of Tolterodine and Pilocarpine—In a separate humanstudy, the combination of tolterodine and pilocarpine was administeredto a healthy human subject. To the subject 2 mg of tolterodine followedby 10 mg of pilocarpine were administered with various delays in theadministration of pilocarpine. Saliva flow was measured as before.Results are shown in FIG. 7.

In one study, 10 mg of pilocarpine was administered to the subject 15minutes after the administration of 2 mg of tolterodine. Saliva flow wasmeasured as before. Results are shown in FIG. 7 (Δ, open triangle). Inanother study, 10 mg of pilocarpine was administered to the subject 22minutes after the administration of 2 mg of tolterodine. Saliva flow wasmeasured as before. Results are shown in FIG. 7 (□, open square). In thelast study, 10 mg of pilocarpine was administered to the subject 30minutes after the administration of 2 mg of tolterodine. Saliva flow wasmeasured as before. Results are shown in FIG. 7 (o, open circle).

As shown in FIG. 7, the decreased in salivary flow caused by tolterodinewas compensated well by the increase in salivary flow induced bypilocarpine. As a result, the amount of salivary flow remained about thesame as the pre-dose level, when pilocarpine was administered 22 minutesafter the administration of tolterodine. FIG. 7 further shows that theamount of salivary flow measured for the combination study, with a 22min delay for pilocarpine, was similar to that of the placebo study.Therefore, administration of 10 mg pilocarpine at 22 minutes after theadministration of 2 mg of tolterodine completely neutralized the adverseside effect of oxybutynin.

Considering that the high doses are not tolerated because of theseverity of the dry mouth, the disclosed approach allows administrationof higher doses of oxybutynin, tolterodine, solifenacin, darifenacin,trospium, fesoterodine, and other approved or compounds in development,thus leading to a more tolerable, effective, and economical treatment.

1. A pharmaceutical composition comprising a therapeutically effectiveamount of oxybutynin, or a free base thereof or a pharmaceuticallyacceptable salt thereof, and pilocarpine, or a free base thereof or apharmaceutically acceptable salt thereof.
 2. The pharmaceuticalcomposition of claim 1, further comprising a pharmaceutically acceptablecarrier, diluent, or excipient.
 3. The pharmaceutical composition ofclaim 1, wherein the oxybutynin, or a free base thereof or apharmaceutically acceptable salt thereof, is present in a dose ofbetween 1 mg to 30 mg.
 4. The pharmaceutical composition of claim 1,wherein the oxybutynin, or a free base thereof or a pharmaceuticallyacceptable salt thereof, is present in a dose of 5 mg.
 5. Thepharmaceutical composition of claim 1, wherein the oxybutynin, or a freebase thereof or a pharmaceutically acceptable salt thereof, is presentin a dose of 10 mg.
 6. The pharmaceutical composition of claim 1,wherein the pilocarpine, or a free base thereof or a pharmaceuticallyacceptable salt thereof, is present in a dose of between 1 mg to 30 mg.7. The pharmaceutical composition of claim 1, wherein the pilocarpine,or a free base thereof or a pharmaceutically acceptable salt thereof, ispresent in a dose of 5 mg.
 8. The pharmaceutical composition of claim 1,wherein the pilocarpine, or a free base thereof or a pharmaceuticallyacceptable salt thereof, is present in a dose of 10 mg.
 9. Apharmaceutical composition comprising a dose of oxybutynin, or a freebase thereof or a pharmaceutically acceptable salt thereof, in the rangeof between 1 mg to 30 mg, in combination with a dose of pilocarpine, ora free base thereof or a pharmaceutically acceptable salt thereof, inthe range of between 1 mg to 30 mg.
 10. The pharmaceutical compositionof claim 9, wherein the oxybutynin, or a free base thereof or apharmaceutically acceptable salt thereof, is present in a dose of 5 mg.11. The pharmaceutical composition of claim 9, wherein the pilocarpine,or a free base thereof or a pharmaceutically acceptable salt thereof, ispresent in a dose of 5 mg.
 12. The pharmaceutical composition of claim9, wherein the oxybutynin, or a free base thereof or a pharmaceuticallyacceptable salt thereof, is present in a dose of 10 mg.
 13. Thepharmaceutical composition of claim 9, wherein the pilocarpine, or afree base thereof or a pharmaceutically acceptable salt thereof, ispresent in a dose of 10 mg.
 14. A pharmaceutical composition comprising5 mg of oxybutynin, or a free base thereof or a pharmaceuticallyacceptable salt thereof, in combination with 5 mg of pilocarpine, or afree base thereof or a pharmaceutically acceptable salt thereof.